Project Summary/Abstract Rural Americans face major health disparities and differences in overall health status, higher rates of chronic disease, geographic isolation, and limited job opportunities. Recent data shows that US rural areas do not experience the consistent decline in premature mortality that non-rural locations do. West Virginia (WV), a highly rural state, exemplifies these disparities and inequities. WV ranks at or near the bottom in many US health indicators (e.g., cardiovascular and cancer morbidity/mortality) and their associated risk factors (e.g., obesity, tobacco use). WV is also at the epicenter of the US opioid crisis. Since 1995, the WV Prevention Research Center has been a transformative force that conducts and translates innovative community-engaged research and evaluation into practical solutions to improve health in WV and beyond. Together with our committed and experienced Community Partnership Board, we propose a Research and Translation Agenda that builds on our expertise in substance use/abuse (especially tobacco and opioids), promotes healthy lifestyles, and fosters youth and community resilience. This Agenda reflects the priorities of our partners and emphasizes policy and practice translation. Our experience with development and national dissemination of the evidence-based teen smoking cessation program, Not on Tobacco, for the American Lung Association, demonstrates our capacity to conduct, translate, and disseminate proven interventions to diverse communities. Our previous partnerships and accomplishments position us for the next 5 years of growth and achievement. We propose to achieve this through the following Specific Aims: 1) sustain and enhance a multidisciplinary infrastructure, inclusive of a statewide Community Partnership Board, that conducts, translates, and disseminates innovative, community- engaged research and evaluation; 2) engage multi-stakeholder partners to develop, implement, and sustain a Research and Translation Agenda, inclusive of a Core Research Project; 3) strengthen the capacity of public health practitioners, health care providers, faculty, staff, students, and communities to conduct and apply prevention research to address public health priorities and disparities through training and service provision; 4) disseminate WVPRC capacity, products, and findings; and 5) participate in the National PRC Network. Our proposed Core Research Project uses a cross-sequential design to address risk and protective factors relevant to youth and community resilience against substance use initiation and progression in middle- and high school-aged youth. This research project is in the public health practice-based evidence research category, incorporates health equity approaches, and attends to the goals of sustainability and scalability. Our intended outcomes include a sustained Center infrastructure; increased capacity in prevention research; and environmental, policy, and practice changes that result in practical, sustainable solutions that improve population health and vitality for years to come.